Correlation Of MPO Gene Polymorphisms, MPO Protein And Coronary Artery Disease

Chapter1Relationship between myeloperoxidase gene polymorphism and coronary artery disease susceptibility: a Meta-analysisBackgroundCoronary artery disease(CAD) susceptibility may be modulated partly through polymorphyisms in oxidative enzymes, one of wich is myeloperoxidase(MPO). Previous studies have evaluated the association between MPO-463G/A、MPO-129G/A gene polymorphism and the risk of CAD, but the results of those studies were inconsistent. This Meta-analysis was conducted to assess the association betweenMPO-463G/A, MPO-129G/A gene polymorphism and CAD and evaluated the association in different ethnicities.ObjectiveTo access relationship between MPO-463G/A、MPO-129G/A gene polymorphism and coronary artery disease.MethodsSeveral electronic databases, such as:PUBMED,Science Citation Index and WANGFANG databases,were be used to search relevant articles up to March2013by the keywords ((MPO OR Myeloperoxidase) AND (genetic polymorphism OR gene OR polymorphism) AND (coronary artery disease OR CAD)). A Meta-analysis was performed by stata11.0software to estimate the pooled odds ratio(OR) and the95%confidence interval(CI).We also assessed heterogeneity and evaluate variations. Different effect models were used according to the difference in heterogeneity. Sensitivity analysis was assessed by omitting one study at a time. Publication bias was examined using Begg’s funnel plot and Egger’s linear regression test.ResultsFinally, a total of17studies on MPO-463G/A and MPO-129G/A gene polymorphisms with CAD risk were included in this meta-analysis. Heterogeneity among studies was tested and sensitivity analysis was applied. For MPO-463G/A polymorphism,15studies including3449cases and3082controls were combined to be analysised. The pooled OR for distribution frequency of A allele was0.58[95%CI(0.47-0.72)] and the pooled OR of genotypes (AA+AG) was0.58,[95%CI (0.46-0.72)]which mean MPO-463G/A allele A was significant associated with CAD. The results of the subgroup analysis in Asia population is the same but in European population is0.79,[95%CI (0.58-1.08)].Three of the17studies describe the risk between MPO-463G/A and subgroup of stable angina pectoris in CAD, including207cases and278controls. Pooled OR of A allele and genotypes (AA+AG) for proven CHD were0.45[95%CI (0.15-1.37)] and1.405,[95%CI(0.21-9.42)]..There are3studies involved1535CAD cases and1655controls investigated MPO-129G/A gene showing that pooled OR for GG genotype is0.86[95%CI:0.64-1.17)].Conclusions A allele of MPO-463G/A polymorphism is significantly associated with a reduced risk of CAD but not in European population only.There was no evidence however, of a significant association between the MPO-129G/A gene polymorphisms and CAD risk. Chapter2Effect of Myeloperoxidase on VasodilatationBackgroundMyeloperoxidase (MPO), existed in the azurophilic granules of neutrophils, monocytes and macrophages, is a highly expressed hemoprotein in neutrophils (5%of neutrophil protein).It’s thought to play a primary role in host defense. Studies have shown that, MPO expression in the plasma was significantly higher in patients with coronary heart disease. It’s one of the biochemical markers of CAD secondary prevention[51]. Meanwhile, MPO also can be detected in atherosclerotic plaques. It’s involved in plaque dynamic changes and vascular pathology and physiological processes. In addition, the MPO levels in CAD patients is related to severity of CAD. All these shows MPO is closely related to coronary atherosclerotic heart disease. At the same time, MPO is proved to be a vascular relaxing factor-nitric oxide (NO) metabolic enzymes. Under physiological conditions, in the presence of H2O2substrate, MPO consumes NO and modulate the balance of NO biological activity.Under pathological conditions, excessive peroxide react with NO directly and generate peroxynitrite. NO is oxidized to nitrite by oxidative enzyme catalyzing. All of that decreased biological activity of NO. MPO-derived HC10can modificate L-arginine which can generate NO. Substrate concentration decreasing can impact NO generation directly. NO generation and inactivation anomalous may result in endothelial dysfunction and vascular diastolic dysfunction. So, we have reasons to speculate that the role of MPO in CAD may be related to its regulation of NO metabolic which can lead to vascular dysfunction.ObjectiveInvestigate the effect of myeloperoxidase on endothelium-dependent and endothelium-independent vasodilation. MethodsThe experiment was divided into three parts:1) the effect of MPO on endothelium-dependent vasodilation;2) the effect of MPO on endothelium-independent vasodilation;3) LMWH reduce endothelial dysfunction induced by MPO. Precontracting vitro SD rat thoracic aortic rings with phenylephrine (PE) and observing the relaxation response of aortic rings in the presence of Acetylcholine (Ach) and Sodium Nitroprusside (SNP). Ach can promote endothelium-derived NO production.SNP is an exogenous NO donor. MPO vascular rings were pre-incubated with MPO, then observing changes of vasodilatory effects induced by Ach and SNP. Observed relaxation response of vascular rings with different Ach concentration. After incubated with MPO and MPO+Low Molecular Heparin (LMWH), observing the changes of vascular ring relaxation response induced by different concentration of Ach.Results1) MPO can reduce endothelium-dependent vasodilation effect induced by Acetylcholine2) MPO damages SNP-induced endothelium-independent vasodilation function3) LMWH can reduce endothelial dysfunction induced by MPOConclusionsMPO may reduce Acetylcholine-induced endothelium-dependent and exogenous NO donor Sodium Nitroprusside-induced endothelium-independent vasodilation, which may result in vascular dysfunction.